arXiv Quantitative Biology @arxiv_bio@qoto.org

Substrate modification networks are ubiquitous in living, biochemical systems. A higher-level hypergraph "skeleton" captures key information about which substrates are transformed in the presence of modification-specific enzymes. Many different detailed models can be associated to the same skeleton, however uncertainty related to model fitting increases with the level of detail. We show that essential dynamical properties such as existence of positive steady states and concentration robustness can be extracted directly from the skeleton independent of the detailed model. The novel formalism of directed hypergraphs is used to prove that bifunctional enzyme action plays a key role in generating robustness. Moreover, we use another novel concept of "current" on a directed hypergraph to establish a link between potentially remote network components. Current is an essential notion required for existence of positive steady states, and furthermore, current-balance combined with bifunctionality generates concentration robustness.

This work introduces the generative fractional diffusion model for protein generation (ProT-GFDM), a novel generative framework that employs fractional stochastic dynamics for protein backbone structure modeling. This approach builds on the continuous-time score-based generative diffusion modeling paradigm, where data are progressively transformed into noise via a stochastic differential equation and reversed to generate structured samples. Unlike classical methods that rely on standard Brownian motion, ProT-GFDM employs a fractional stochastic process with superdiffusive properties to improve the capture of long-range dependencies in protein structures. Trained on protein fragments from the Protein Data Bank, ProT-GFDM outperforms conventional score-based models, achieving a 7.19% increase in density, a 5.66% improvement in coverage, and a 1.01% reduction in the Frechet inception distance. By integrating fractional dynamics with computationally efficient sampling, the proposed framework advances generative modeling for structured biological data, with implications for protein design and computational drug discovery.

The article covers the continuous McKendrick model, which is key in epidemiology and population dynamics, developed by Anderson Gray McKendrick. It describes population age structure changes via birth and death rates as continuous functions, shedding light on population dynamics through differential equations. The article delves into the equations, boundary conditions, and survival rates, offering insights into disease progression and population dynamics. It aims for an asymptotic analysis of population dynamics using previous studies and illustrative examples. The main finding is that the population nears extinction only if the expected offspring per individual ($R$) is less than 1.

Inference of phylogenetic networks is of increasing interest in the genomic era. However, the extent to which phylogenetic networks are identifiable from various types of data remains poorly understood, despite its crucial role in justifying methods. This work obtains strong identifiability results for large sub-classes of galled tree-child semidirected networks. Some of the conditions our proofs require, such as the identifiability of a network's tree of blobs or the circular order of 4 taxa around a cycle in a level-1 network, are already known to hold for many data types. We show that all these conditions hold for quartet concordance factor data under various gene tree models, yielding the strongest results from 2 or more samples per taxon. Although the network classes we consider have topological restrictions, they include non-planar networks of any level and are substantially more general than level-1 networks -- the only class previously known to enjoy identifiability from many data types. Our work establishes a route for proving future identifiability results for tree-child galled networks from data types other than quartet concordance factors, by checking that explicit conditions are met.

Premature birth and various pre- and peri-natal stresses can lead to a variety of brain lesions and have clearly been identified as major risk factors for neurodevelopmental disorders, with variable but multiple consequences that can significantly alter the functional outcome of children in the short, medium and long term. The main aim of the various diagnostic and prognostic markers available, based in particular on clinical and neuroimaging data, is to facilitate early detection of the various disorders and to optimise the follow-up and management of these babies at risk of deficiencies.

Human brain development is a complex and dynamic process that begins during the first weeks of pregnancy and lasts until early adulthood. This chapter focuses on the developmental window from prenatal period to infancy, probably the most dynamic period across the entire lifespan. The availability of non-invasive three-dimensional Magnetic Resonance Imaging (MRI) methodologies has changed the paradigm and allows investigations of the living human brain structure - e.g. micro- and macrostructural features of cortical and subcortical regions and their connections, including cortical sulcation/gyrification, area, and thickness, as well as white matter microstructure and connectivity - beginning in utero. Because of its relative safety, MRI is well-adapted to study individuals at multiple time points and to longitudinally follow the changes in brain structure and function that underlie the early stages of cognitive development.

Diabetes is a civilization chronic disease characterized by a constant elevated concentration of glucose in the blood. Many processes are involved in the glucose regulation, and their interactions are very complex. To better understand those processes we set ourselves a goal to create a Petri net model of the glucose regulation in the whole body. So far we have managed to create a model of glycolysis and synthesis of glucose in the liver, and the general overview models of the glucose regulation in a healthy and diabetic person. In this paper we introduce Petri nets models of insulin secretion in beta cell of the pancreas, and glucagon in the pancreas alpha cells. Those two hormones have mutually opposite effects: insulin preventing hyperglycemia, and glucagon preventing hypoglycemia. Understanding the mechanisms of insulin and glucagon secretion constitutes the basis for understanding diabetes. We also present a model in which both processes occur together, depending on the blood glucose level. The dynamics of each model is analysed. Additionally, we transform the overall insulin and glucagon secretion system to a Boolean network, following standard transformation rules.

Virtual reality (VR) is increasingly used to enhance the ecological validity of motor control and learning studies by providing immersive, interactive environments with precise motion tracking. However, designing realistic VR-based motor tasks remains complex, requiring advanced programming skills and limiting accessibility in research and clinical settings. MovementVR is an open-source platform designed to address these challenges by enabling the creation of customizable, naturalistic reaching tasks in VR without coding expertise. It integrates physics-based hand-object interactions, real-time hand tracking, and flexible experimental paradigms, including motor adaptation and reinforcement learning. The intuitive graphical user interface (GUI) allows researchers to customize task parameters and paradigm structure. Unlike existing platforms, MovementVR eliminates the need for scripting while supporting extensive customization and preserving ecological validity and realism. In addition to reducing technical barriers, MovementVR lowers financial constraints by being compatible with consumer-grade VR headsets. It is freely available with comprehensive documentation, facilitating broader adoption in movement research and rehabilitation.

Bone marrow stromal cells (BMSCs), whose populations contain multipotent skeletal stem cells with relevant therapeutic applications, are known to produce very heterogeneous colonies upon in vitro culture, a trait that may severely hinder the clinical usefulness of BMSC-based therapies. Therefore, reaching a better insight on the nature of such heterogeneity, as well as on the factors determining it, is important. Here, by using time-lapse microscopy, we study the structure of N=28 human BMSC colonies from six donors, each colony derived from a single cell, and trace their lineage trees up to the seventh generation. We confirm the presence of very significant inter-colony and intra-colony heterogeneities, both in the topology of the lineages and in the replicative kinetics of the colonies. We also find that topology and kinetics are strongly correlated, consistent with the existence of regulating factors linking the sub-population of inactive cells, which uniquely determine a lineage's topology, and that of active cells, which are the sole responsible for the proliferation rate of the colony. Finally, we submit each colony to an entropy-based inheritance test, which measures the degree of non-random clustering of inactive cells within the same branches of the lineage, and find a clear signature of hereditary transmission of the probability of emergence of inactive cells in the largest majority of the experimental lineages.

Objective: A number of machine learning models have utilized semantic features, deep features, or both to assess lung nodule malignancy. However, their reliance on manual annotation during inference, limited interpretability, and sensitivity to imaging variations hinder their application in real-world clinical settings. Thus, this research aims to integrate semantic features derived from radiologists' assessments of nodules, allowing the model to learn clinically relevant, robust, and explainable features for predicting lung cancer. Methods: We obtained 938 low-dose CT scans from the National Lung Screening Trial with 1,246 nodules and semantic features. The Lung Image Database Consortium dataset contains 1,018 CT scans, with 2,625 lesions annotated for nodule characteristics. Three external datasets were obtained from UCLA Health, the LUNGx Challenge, and the Duke Lung Cancer Screening. We finetuned a pretrained Contrastive Language-Image Pretraining model with a parameter-efficient fine-tuning approach to align imaging and semantic features and predict the one-year lung cancer diagnosis. Results: We evaluated the performance of the one-year diagnosis of lung cancer with AUROC and AUPRC and compared it to three state-of-the-art models. Our model demonstrated an AUROC of 0.90 and AUPRC of 0.78, outperforming baseline state-of-the-art models on external datasets. Using CLIP, we also obtained predictions on semantic features, such as nodule margin (AUROC: 0.81), nodule consistency (0.81), and pleural attachment (0.84), that can be used to explain model predictions. Conclusion: Our approach accurately classifies lung nodules as benign or malignant, providing explainable outputs, aiding clinicians in comprehending the underlying meaning of model predictions. This approach also prevents the model from learning shortcuts and generalizes across clinical settings.

Drug-target interaction (DTI) prediction is a core task in drug development and precision medicine in the biomedical field. However, traditional machine learning methods generally have the black box problem, which makes it difficult to reveal the deep correlation between the model decision mechanism and the interaction pattern between biological molecules. This study proposes a heterogeneous network drug target interaction prediction framework, integrating graph neural network and multi scale signal processing technology to construct a model with both efficient prediction and multi level interpretability. Its technical breakthroughs are mainly reflected in the following three dimensions:Local global feature collaborative perception module. Based on heterogeneous graph convolutional neural network (HGCN), a multi order neighbor aggregation strategy is designed.Multi scale graph signal decomposition and biological interpretation module. A deep hierarchical node feature transform (GWT) architecture is proposed.Contrastive learning combining multi dimensional perspectives and hierarchical representations. By comparing the learning models, the node representations from the two perspectives of HGCN and GWT are aligned and fused, so that the model can integrate multi dimensional information and improve the prediction robustness. Experimental results show that our framework shows excellent prediction performance on all datasets. This study provides a complete solution for drug target discovery from black box prediction to mechanism decoding, and its methodology has important reference value for modeling complex biomolecular interaction systems.

Discovering molecules with desirable molecular properties, including ADMET (Absorption, Distribution, Metabolism, Excretion, and Toxicity) profiles, is of great importance in drug discovery. Existing approaches typically employ deep learning models, such as Graph Neural Networks (GNNs) and Transformers, to predict these molecular properties by learning from diverse chemical information. However, these models often fail to efficiently capture and utilize the hierarchical nature of molecular structures, and lack mechanisms for effective interaction among multi-level features. To address these limitations, we propose a Hierarchical Interaction Message Passing Mechanism, which serves as the foundation of our novel model, HimNet. Our method enables interaction-aware representation learning across atomic, motif, and molecular levels via hierarchical attention-guided message passing. This design allows HimNet to effectively balance global and local information, ensuring rich and task-relevant feature extraction for downstream property prediction tasks, such as Blood-Brain Barrier Permeability (BBBP). Extensive experiments on multiple benchmark datasets demonstrate that HimNet achieves the best or near-best performance in most molecular property prediction tasks. Furthermore, our method exhibits promising hierarchical interpretability, aligning well with chemical intuition on representative molecules. We believe that HimNet offers an accurate and efficient solution for molecular activity and ADMET property prediction, contributing significantly to advanced decision-making in the early stages of drug discovery.

Background: Praying mantises, members of the order Mantodea, play important roles in agriculture, medicine, bionics, and entertainment. However, the scarcity of genomic resources has hindered extensive studies on mantis evolution and behaviour. Results: Here, we present the chromosome-scale reference genomes of five mantis species: the European mantis (Mantis religiosa), Chinese mantis (Tenodera sinensis), triangle dead leaf mantis (Deroplatys truncata), orchid mantis (Hymenopus coronatus), and metallic mantis (Metallyticus violaceus). We found that transposable element expansion is the major force governing genome size in Mantodea. Based on whole-alignments, we deduced that the Mantodea ancestor may have had only one X chromosome and that translocations between the X chromosome and an autosome may have occurred in the lineage of the superfamily Mantoidea. Furthermore, we found a lower evolutionary rate for the metallic mantis than for the other mantises. We also found that Mantodea underwent rapid radiation after the K-Pg mass extinction event, which could have contributed to the confusion in species classification. Conclusions: We present the chromosome-scale reference genomes of five mantis species to reveal the X-chromosome evolution, clarify the phylogeny relationship, and transposable element expansion.

Recent advances in self-supervised learning have attracted significant attention from both machine learning and neuroscience. This is primarily because self-supervised methods do not require annotated supervisory information, making them applicable to training artificial networks without relying on large amounts of curated data, and potentially offering insights into how the brain adapts to its environment in an unsupervised manner. Although several previous studies have elucidated the correspondence between neural representations in deep convolutional neural networks (DCNNs) and biological systems, the extent to which unsupervised or self-supervised learning can explain the human-like acquisition of categorically structured information remains less explored. In this study, we investigate the correspondence between the internal representations of DCNNs trained using a self-supervised contrastive learning algorithm and human semantics and recognition. To this end, we employ a few-shot learning evaluation procedure, which measures the ability of DCNNs to recognize novel concepts from limited exposure, to examine the inter-categorical structure of the learned representations. Two comparative approaches are used to relate the few-shot learning outcomes to human semantics and recognition, with results suggesting that the representations acquired through contrastive learning are well aligned with human cognition. These findings underscore the potential of self-supervised contrastive learning frameworks to model learning mechanisms similar to those of the human brain, particularly in scenarios where explicit supervision is unavailable, such as in human infants prior to language acquisition.

Biological time can be measured in two ways: in generations and in physical time. When generation intervals differ between individuals, these two clocks diverge, which impedes our ability to relate mathematical models to real populations. In this paper we show that nevertheless, these disparate clocks become equivalent in the long run via a simple identity relating generational and physical time. This equivalence allows us to directly translate statements from mathematical models to the physical world and vice versa. As an application, we obtain a generalized Euler-Lotka equation linking the basic reproduction number $R_0$ to the growth rate, and derive several information-theoretic bounds on these quantities. We also show how the fitness of a lineage can be defined consistently in population models, with applications to microbial growth, epidemiology and population biology.

The metapopulation theory explores the population persistence in fragmented habitats by considering a balance between the extinction of local populations and recolonization of empty sites. In general, the extinction and colonization rates have been considered as constant parameters and the novelty of this paper is to assume that they are subject to deterministic variations. We noticed that an averaging approach proposed by C. Puccia and R. Levins can be adapted to construct the upper and lower averages of the difference between the extinction and colonization rates, whose sign is useful to determine either the permanence or the extinction of the metapopulation. In fact, we use these averages to revisit the classical model introduced by R. Levins. From a mathematical perspective, these averages can be seen as Bohl exponents whereas the corresponding analysis is carried out by using tools of non autonomous dynamics. Last but not least, compared with the Levins model, the resulting dynamics of the time varying model shares the persistence/extinction scenario when the above stated upper and lower averages have the same sign but also raises open questions about metapopulation persistence in the case of the averages have different sign.

In the human brain, white matter development is a complex and long-lasting process involving intermingling micro-and macrostructural mechanisms, such as fiber growth, pruning and myelination. Did you know that all these neurodevelopmental changes strongly affect MRI signals, with consequences on tractography performances and reliability? This communication aims to elaborate on these aspects, highlighting the importance of tracking and studying the developing connections with dedicated approaches.

Protein sequence analysis underpins research in biophysics, computational biology, and bioinformatics. We introduce BEER, a crossplatform graphical interface that accepts FASTA or Protein Data Bank (PDB) files, or manual sequence entry, and instantly computes a suite of physicochemical metrics, such as amino acid composition, Kyte Doolittle hydrophobicity profiles, net charge versus pH curves with automatic isoelectric point determination, solubility predictions, and key indices such as molecular weight, extinction coefficient, GRAVY (grand average of hydropathicity) score, instability index, and aromaticity. BEER's interactive visualizations, including bar and pie charts, hydropathy plots, residue level bead models, and radar diagrams make it easy to explore physicochemical properties of protein chains. A multichain module also enables direct comparison of complex assemblies. Built in Python with BioPython, PyQt5, and matplotlib, BEER delivers complete analyses of sequences up to 10000 residues in under one second.

Computational modeling of multicellular systems may aid in untangling cellular dynamics and emergent properties of biological cell populations. A key challenge is to balance the level of model detail and the computational efficiency, while using physically interpretable parameters to facilitate meaningful comparisons with biological data. For this purpose, we present the DLCM-solver (discrete Laplacian cell mechanics), a flexible and efficient computational solver for spatial and stochastic simulations of populations of cells, developed from first principle to support mechanistic investigations. The solver has been designed as a module in URDME, the unstructured reaction-diffusion master equation open software framework, to allow for the integration of intra-cellular models with extra-cellular features handled by the DLCM. The solver manages discrete cells on a fixed lattice and reaction-transport events in a continuous-time Markov chain. Space-continuous micro-environment quantities such as pressure and chemical substances are supported by the framework, permitting a variety of modeling choices concerning chemotaxis, mechanotaxis, nutrient-driven cell growth and death, among others. An essential and novel feature of the DLCM-solver is the coupling of cellular pressure to the curvature of the cell populations by elliptic projection onto the computational grid, with which we can include effects from surface tension between populations. We demonstrate the flexibility of the framework by implementing benchmark problems of cell sorting, cellular signaling, tumor growth, and chemotaxis models. We additionally formally analyze the computational complexity and show that it is theoretically optimal for systems based on pressure-driven cell migration. In summary, the solver balances efficiency and a relatively fine resolution, while supporting a high level of interpretability.

Motivation: Computational models in biology can increase our understanding of biological systems, be used to answer research questions, and make predictions. Accessibility and reusability of computational models is limited and often restricted to experts in programming and mathematics. This is due to the need to implement entire models and solvers from the mathematical notation models are normally presented as. Implementation: Here, we present SBMLtoOdin, an R package that translates differential equation models in SBML format from the BioModels database into executable R code using the R package odin, allowing researchers to easily reuse models. We also present Menelmacar, a a web-based application that provides interactive visualisations of these models by solving their differential equations in the browser. This platform allows non-experts to simulate and investigate models using an easy-to-use web interface. Availability: SBMLtoOdin is published under open source Apache 2.0 licence at https://github.com/bacpop/SBMLtoOdin and can be installed as an R package. The code for the Menelmacar website is published under MIT License at https://github.com/bacpop/odinviewer, and the website can be found at https://biomodels.bacpop.org/.